Need to know:

  • Following two late-phase Huntington’s disease trial misses, both Roche and Prilenia Therapeutics are using new clinical trial design approaches in a bid for positive study results. Prilenia, specifically, changed its primary endpoint in response to new information about its drug’s mechanism.
  • Overall, to maximise their success chances, late-stage Huntington’s disease trials should last more than one year, pursue biomarkers of disease activity, and target patients with early-stage disease.
  • Expected Phase II readouts from Annexon Biosciences and Wave Life Sciences round out this year’s crop of drug development data readouts for Huntington’s disease, which has no FDA-approved, disease-modifying therapy.

The past several years have seen a series of high-profile Huntington’s disease (HD) clinical trial misses. In March 2021, Roche reported that its Phase III study of tominersen had ended prematurely. During the same month, Wave Life Sciences announced two of its antisense oligonucleotide candidates did not have any anticipated effects on slowing HD disease progression. In February 2019, Prilenia Therapeutics revealed that pridopidine fell short of its primary outcome in a Phase II study.

By adjusting the primary endpoints and target patient populations, the HD candidates from Roche and Prilenia could be back on track with two new clinical trials. In addition, Annexon Biosciences’ ANX-005 and Wave’s third HD asset WVE-003 expect readouts this year for their safety-focused clinical trials.

Because HD is a neurodegenerative disease that slowly advances over decades, it can prove challenging to detect changes in disease progression during a relatively short-term clinical trial. The lack of validated biomarkers of disease state or progression, combined with uncertainty over mechanistic targets, only compounds this difficulty.

Still, there are strategies for maximising chances at success. Drug developers should target the early stage HD population, research potential biomarkers like striatal atrophy, and schedule trials for more than one year to satisfy regulators. This year’s upcoming HD drug trial readouts will shed light on whether these approaches could help the field bounce back from a series of failed attempts.

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Huntington's disease requires long trials

Both European regulators and the FDA accept statistically significant improvement in the Unified Huntington’s Disease Rating Scale – Total Functional Capacity (UHDRS-TFC) as a single primary endpoint for an approval in HD, says Prilenia Therapeutics CEO Michael Hayden. The UHDRS-TFC measures how patients manage work, finances, daily living, domestic chores, and care arrangements.

To detect a slowing of HD progression via UDHRS-TFC, clinical trials should be 1.5–3 years long, notes Dr Christopher Ross, director of neurobiology at John Hopkins Medicine. Because UDHRS-TFC is just a 13-point scale, it is fairly insensitive to changes in HD disease progression, he adds. However, any statistically significant change along UHDRS-TFC is sure to be clinically relevant, he explains.

Prilenia has a Phase III trial underway in HD, using UHDRS-TFC over 65 weeks as the primary endpoint. Prilenia’s Hayden says the FDA recommended a trial length of at least 52 weeks, and European regulators asked the trial to go even longer.

Enrolment can prove lengthy in Huntington's disease

HD is tough to diagnose early and only affects approximately one in 10,000 people in the US, making clinical trial enrolment lengthy. In fact, according to GlobalData’s clinical trials database, Phase I to Phase III drug trials in HD between 2015 and 2020 averaged longer enrolment periods than treatment periods. The average Phase I trial had a 17.2-month enrolment period, while the average treatment period was 2.6 months.

However, Phase III trials average shorter enrolment periods than earlier stage studies. While the average enrolment time is 15.1 months in a Phase III study, the average treatment period is 12.7 months.

Nonetheless, people with HD are typically very enthusiastic to take part in clinical trials for the fatal disease, Ross notes. Overall, finding willing participants is not a significant issue, he adds.

Prilenia’s Phase III trial of pridopidine surpassed its enrollment goal of 480 patients and recruited six weeks ahead schedule, the company’s CEO Hayden says. The study has 58 sites throughout the US, Canada, and Europe.

Targeting early disease optimises trials

To maximise the chance of detecting changes via UHDRS-TFC, most HD trials should target patients in earlier stage HD, Hayden explains. UHDRS-TFC declines more rapidly in early stage HD, making it easier to detect change relative to placebo along the scale, he adds. Both Roche and Prilenia have placebo-controlled studies.

Overall, HD has five stages that typically progress over the course of 10 to 30 years from disease emergence. A UHDRS-TFC score of 11–13 means the patient has the least severe symptoms, while a score of 0 is the most severe. UHDRS-TFC typically lowers by around one point if the patient is in Stage I, by 0.8 in Stage 2, by 0.3 in Stage 3, and by 0.1 in Stage 4, Hayden explains.

Prilenia’s trial is recruiting Stage I or 2 patients, defined as a UHDRS-TFC score of 7 or higher at screening. Roche has not yet revealed its complete trial design details. It did not reply to a comment request.

Striatal atrophy, a hallmark of HD, can already arise 10–15 years before HD symptoms manifest, Ross notes. As such, HD may be too late to target by the time visible symptoms appear, he explains.

Biomarkers in development

The field is eager to begin trials even earlier, in the presymptomatic HD population. However, it is difficult to select an outcome measure for patients without diagnosable HD. Drug developers could attempt long trials aimed at delaying the onset of HD, but ideally the FDA would allow biomarkers or surrogate markers for disease progression, Ross says.

The FDA could eventually accept a marker like striatal atrophy, but the agency would need a successful HD trial to link this biomarker to actual improvement in UHDRS-TFC, Ross adds. The ongoing Phase III trial for pridopidine does not have the magnetic resonance imaging (MRI) testing necessary to potentially measure striatal atrophies correlation with HD progression, he notes. There is currently no approved disease-modifying therapy in HD.

Neurofilament light chain (NfL), a biomarker that is also in development for the neurodegenerative disease ALS, could serve as a measure of HD disease onset if it gains more supporting evidence, Hayden notes. NfL is a blood biomarker that could be correlated with neurodegeneration in the central nervous system.

New endpoint for Prilenia’s pridopidine

Prilenia’s pridopidine has 499 patients enrolled in the Phase III PROOF-HD trial (NCT04556656), which tests UHDRS-TFC after 65 weeks as its primary endpoint. Results for the Phase III study, which has FDA fast track designation, are expected in early 2023. The drug has a 2027 sales forecast of $79m, according to GlobalData’s peak sales consensus estimates.

Before beginning the Phase III trial, pridopidine missed the primary endpoint in a 408-patient Phase II trial (NCT02006472). The Phase II used UHDRS – Total Motor Score (UHDRS-TMS) as its primary endpoint. Prilenia originally thought pridopidine could improve motor symptoms in HD by targeting dopamine receptors, Prelinia’s Hayden says. However, the company subsequently realised that pridopidine had potentially neuroprotective effects by targeting the sigma-1 receptor (S1R), which explains the change in endpoint in Phase III, he explains.

The current Phase III uses UHDRS-TFC instead of UHDRS-TMS because the former is better at detecting a slowing of disease progression, Hayden adds. As for the Phase III’s trial success prospects, Ross says there is a compelling biological case that pridopidine could have neuroprotective effects by targeting S1R. S1R is a ligand-operated protein situated in endoplasmic reticulum membranes, with its change in function and/or expression associated with various neurological disorders such as Huntington’s disease.

Roche to come back with new trial

As for Roche’s Phase III GENERATION HD1 trial (NCT03761849), the study halted early last year following a recommendation from an independent data monitoring committee. However, the development partners Roche and Ionis announced on January 18 that they are designing a Phase II trial of tominersen in HD.

Exploratory post-hoc tominersen analyses suggest that it may benefit younger adult patients with lower disease burden, a Roche spokesperson says. Roche and Ionis are currently in the early stages of designing a multiple-dose Phase II trial to test this new hypothesis, she adds. The company will share further details about the GENERATION HD1 data findings and design of the new Phase II at a future scientific meeting, she notes.

The 899-patient GENERATION HD1 study had coprimary endpoints of UHDRS-TFC and Composite UHDRS (cUHDRS), both over 101 weeks. GENERATION HD1 recruited patients ages 25 to 65 years with manifest HD, a term for patients whose symptoms are thought to result from HD. Tominersen has a peak sales forecast of $778m in 2027.

According to Ross, there are two possible explanations for why the Phase III trial failed. One possibility is that tominersen could be knocking down wild-type Huntington and damaging neurons because it is not allele-specific, he notes. This means that any nonallele selective Huntington-lowering agent would have the same problem, potentially eliminating the whole approach, he explains.

There could also be an inflammatory off-target effect, which is more likely the case, Ross says. In the interim analysis of GENERATION HD1, patients in the most frequent dosing group progressed in HD more rapidly than those in the placebo group.

Upcoming safety-driven trial data

As for the other readouts this year, Annexon’s ANX-005 has a 28-patient, open-label, Phase IIa trial (NCT04514367) with results expected in Q2. Wave’s WVE-003 is recruiting for a 36-patient Phase I/IIa trial (NCT05032196), with results also expected this year.

ANX-005 is a complement C1q subcomponent inhibitor. “The theory behind the Annexon compound is that there’s abnormal synaptic pruning during HD, which could be blocked by [Annexon’s] complement inhibitor,” Ross explains. “That’s an enticing idea, and it could potentially target an earlier stage of the disease.” However, synaptic pruning could be a necessary component of memory and learning, so there could be problems with altering it, he adds. Annexon’s ANX-005 has a peak sales estimate of $252m.

WVE-003 targets the Huntington protein (HTT) to slow disease progression. The trial is enrolling patients with early manifest HD who carry single nucleotide polymorphism 3 (SNP3). Although Wave’s previous two HD assets were associated with serious side effects, this third compound has not yet exhibited any serious adverse events (AEs), Ross says. Previous trials show serious AEs included disorientation, delirium, ataxia, and slurred speech.

AE with previous Wave candidates may imply that such issues were related to the chemical backbone rather than the target itself, Ross explains. A Wave spokesperson notes WVE-003 has a different sequence and design compared with the company’s first-generation HD candidates, including the incorporation of phosphoryl guanidine-based backbone chemistry modifications.

Wave's ongoing HD trial is designed differently from its previous two HD trials, the spokesperson adds. The ongoing Phase I/IIa has dose escalation and dosing frequency guided by an independent committee to support data driven decisions regarding dosing, and to potentially accelerate time to proof-of-concept, she notes.

Progress in easing HD symptoms

While the road to developing disease modifying therapies in HD has proven tough, there has been headway in treating HD’s common symptom of chorea. Chorea is a movement disorder characterised by involuntary and unpredictable muscle movement. In December 2021, Neurocrine Biosciences announced that Ingrezza (valbenazine) met its primary endpoint of UHDRS – Total Maximal Chorea (UHDRS-TMC) in the Phase III KINECT-HD trial (NCT04102579).

Ingrezza is likely to gain approval because the data on chorea is strong and the mechanism is clear, Hayden says. Depleting presynaptic dopamine has an impact on chorea, although it has no effect on function or disease progression, he notes. Ingrezza, which is a vesicular monoamine transporter 2 (VMAT2) inhibitor, already has an FDA approval for the treatment of tardive dyskinesia.

If Ingrezza does gain a regulatory nod in HD, the drug would join Lundbeck’s Xenazine (tetrabenazine) and Teva Pharmaceutical’s Austedo (deutetrabenazine) as FDA-approved drugs for treating chorea. They are also the only approved drugs for HD overall. In the meantime, the quest for a disease-modifying treatment continues.


  • Prilenia is using UHDRS-TFC as the primary endpoint in its Phase III study after evidence from a Phase II trial suggested that pridopidine has neuroprotective effects. The Phase II trial failed but used a different endpoint.
  • Roche plans to continue testing tominersen in a Phase II trial in younger, early stage HD patients based on a post hoc analyses from a Phase III trial that was terminated early. Full trial design is not yet revealed.
  • Annexon’s ANX-005 and Wave’s WVE-003 are in early stages of development, with companies amid safety-focused Phase II trials.

Note: This article has been updated to reflect the correct date for the impending results of Prilenia Therapeutics' Phase III trial. A previous version stated results were expected in 2022.